Mesalamine suppository

ABSTRACT

The present invention relates to a mesalamine rectal suppository designed to provide improved comfort of use. One embodiment of the invention is a mesalamine rectal suppository comprising mesalamine and one or more pharmaceutically acceptable excipients, wherein the drug load of the suppository ranges from 35% to 50%. Yet another embodiment of the invention is a mesalamine rectal suppository comprising mesalamine having a tap density ranging from about 600 to about 800 g/L (as measured by USP &lt;616&gt;) and a hard fat having an ascending melting point of 32 to 35.5° C. Yet another embodiment is a mesalamine rectal suppository comprising mesalamine particles and one or more pharmaceutically acceptable excipients, where the mesalamine particles have a surface area of from about 0.1 m 2 /g to about 2.8 m 2 /g (e.g., from about 0.1 m 2 /g to about 1.3 m 2 /g). Methods of preparing and methods of treatment with mesalamine suppositories are also provided. The invention further provides a method of determining a dissolution parameter (such as dissolution rate) of a mesalamine rectal suppository, such as a 1 g mesalamine suppository, by measuring its dissolution with USP Apparatus #2 at 40° C. and a paddle rotation speed of 125 rpm in 0.2 M phosphate buffer at a pH of 7.5.

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/476,185, filed Jun. 1, 2009, which is a continuation-in-partof U.S. patent application Ser. No. 12/245,648, filed Oct. 3, 2008 (nowU.S. Pat. No. 7,541,384), which is a continuation of U.S. patentapplication Ser. No. 12/135,103, filed Jun. 6, 2008, and claims thebenefit of U.S. Provisional Application No. 60/943,029, filed Jun. 8,2007, all of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a mesalamine suppository designed toprovide improved comfort of use, a method for manufacturing it, andmethods for treating ulcerative colitis, such as active ulcerativeproctitis, with it as well as a method of measuring a dissolutionparameter of a mesalamine suppository.

BACKGROUND OF THE INVENTION

Inflammatory bowel diseases (IBD), such as Crohn's disease andulcerative colitis (UC), are characterized by chronic, relapsingintestinal inflammation. Crohn's disease and UC are believed to involvea dysregulated immune response to gastrointestinal (GI) tract antigens,a mucosal barrier breach, and/or an adverse inflammatory reaction to apersistent intestinal infection. In normal people, the GI tract luminalcontents and bacteria constantly stimulate the mucosal immune system,and a delicate balance of pro-inflammatory and anti-inflammatory cellsand molecules maintains the integrity of the GI tract, without elicitingsevere and damaging inflammation [MacDermott, R. P., J Gastroenterology,31:907-916 (1996)]. It is unknown how the IBD inflammatory cascadebegins, but constant GI antigen-dependent stimulation of the mucosal andsystemic immune systems perpetuates the inflammatory cascade and driveslesion formation.

UC is a non-specific inflammatory disease of the colon that is ofunknown cause and is characterized by diarrhea with discharge of mucusand blood, cramping abdominal pain, and inflammation and edema of themucous membrane with patches of ulceration. UC limited to the rectum isknown as ulcerative proctitis. People suffering from chronic UCaffecting the whole colon have an increased risk of colonic cancer.Furthermore, when medical therapy fails, surgical resection of affectedbowel may be necessary.

In patients with more extensive disease, blood loss from the inflamedintestines can lead to anemia, and may require treatment with ironsupplements or even blood transfusions. Although infrequent, the coloncan acutely dilate to a large size when the inflammation becomes verysevere. This condition is called toxic megacolon. Patients with toxicmegacolon are extremely ill with fever, abdominal pain and distention,dehydration, and malnutrition. Unless the patient improves rapidly withmedication, surgery is usually necessary to prevent colon rupture andhigh risk of death.

Mesalamine, 5-aminosalicylic acid (5-ASA), is often used to treat UC andis effective in reducing disease symptoms and the incidence of relapsein UC. While mesalamine is available in oral form, intrarectaladministration of it has several advantages. For example, rectaladministration of a drug avoids some side-effects, such asgastrointestinal disorders, due to oral administration. As mesalamine isa locally GI active drug, lower doses of the drug can be administeredrectally to obtain a better or equivalent therapeutic effect as thatattained with a higher dose oral formulation. The absorption of a drugorally administered may also be affected by whether it is administeredbefore or after each meal or between meals. There is no such food effectwhen drugs are administered intrarectally. Intrarectal administrationcan be performed even during nausea, vomiting or unconsciousness, orafter surgical operation.

A 1 g mesalamine suppository of a substantial size (3 g) is currentlymarketed in the U.S. by Axcan Scandipharm Inc. as CANASA® for thetreatment of active ulcerative proctitis.

There is a need for mesalamine suppositories which provide increasedcomfort of use.

SUMMARY OF THE INVENTION

The present inventors have discovered that the size of a mesalaminesuppository can be drastically reduced (for example, by over 20% byweight) and the melting point lowered without a substantial adverseeffect on its dissolution profile or its overall therapeutic efficacy.The combination of a smaller suppository and a lower melting temperatureprovides increased comfort of use. The inventors discovered that thisresult can be obtained by increasing the tap density of the mesalamineand, preferably, also lowering the melting point of the suppositorybase.

Generally when the drug load of a mesalamine suppository is increased,so too is the viscosity of the molten suspension which is cast to formthe suppository. If the viscosity of the mesalamine suspension is toohigh, it cannot be cast into a suppository having acceptable contentuniformity and good therapeutic properties. The inventors havesurprisingly found that the viscosity of the measlamine suspension canbe decreased by increasing the tap density of the mesalamine.

The inventors have also surprisingly discovered that the dissolutionrate of mesalamine (a poorly soluble drug) from a suppository increasesas surface area of the mesalamine particles decreases. This is contraryto the common scientific belief that the dissolution rate of a drugincreases as the surface area of the drug particles increases.

One embodiment of the present invention is a mesalamine rectalsuppository comprising mesalamine and one or more pharmaceuticallyacceptable excipients, wherein the drug load of the suppository rangesfrom about 35% to about 50% and preferably from about 37% to about 46%.The suppository may include from about 850 to about 1150 mg mesalamine,and preferably includes about 950 mg to about 1050 mg mesalamine (andeven more preferably about 1000 mg mesalamine). According to anotherembodiment, the suppository includes from about 400 to about 600 mgmesalamine, and preferably includes about 450 to about 550 mg mesalamine(and even more preferably about 500 mg mesalamine). According to yetanother embodiment, the suppository includes from about 1400 to about1600 mg mesalamine, and preferably includes about 1450 to about 1550 mgmesalamine (and even more preferably about 1500 mg mesalamine). Themesalamine suppository may further include a suppository base, such ashard fat (e.g., hard fat NF).

Another embodiment of the invention is a mesalamine rectal suppositorycomprising from about 850 to about 1150 mg mesalamine and one or morepharmaceutically acceptable excipients, wherein the total weight of thesuppository ranges from about 2250 to about 2700 mg. Preferably, thetotal weight of the suppository ranges from about 2250 to about 2500 mg.The amount of mesalamine in the suppository preferably ranges from about950 mg to about 1050 mg and more preferably is about 1000 mg. Themesalamine suppository may further include a suppository base, such ashard fat (e.g., hard fat NF).

Another embodiment of the invention is a mesalamine rectal suppositorycomprising from about 400 to about 600 mg mesalamine and one or morepharmaceutically acceptable excipients, wherein the total weight of thesuppository ranges from about 870 to about 1715 mg. Preferably, thetotal weight of the suppository ranges from about 980 to about 1570 mg.Preferably, the drug load is from about 35% to about 50%. The amount ofmesalamine in the suppository preferably ranges from about 450 mg toabout 550 mg and more preferably is about 500 mg. The mesalaminesuppository may further include a suppository base, such as hard fat(e.g., hard fat NF).

Yet another embodiment of the invention is a mesalamine rectalsuppository comprising from about 1400 to about 1600 mg mesalamine andone or more pharmaceutically acceptable excipients, wherein the totalweight of the suppository ranges from about 2800 to about 4570 mg.Preferably, the total weight of the suppository ranges from about 3000to about 4200 mg. Preferably, the drug load is from about 35% to about50%. The amount of mesalamine in the suppository preferably ranges fromabout 1450 mg to about 1550 mg and more preferably is about 1500 mg. Themesalamine suppository may further include a suppository base, such ashard fat (e.g., hard fat NF). The mesalamine in each of theaforementioned suppositories preferably has a tap density ranging fromabout 600 to about 800 g/L (as measured by USP <616>) and/or a surfacearea of from about 0.1 to about 2.8 m²/g (or preferably from about 0.2to about 2.8 m²/g, preferably from about 0.1 to about 1.3 m²/g, orpreferably from about 0.2 to about 1.3 m²/g). According to a preferredembodiment, the mesalamine in the aforementioned suppositories isdispersed in a low melting suppository base (i.e., a suppository basehaving an ascending melting point of no more than 35.5° C.). A preferredlow melting suppository base is hard fat having an ascending meltingpoint of 32 to 33.5° C. (e.g., Witepsol® H 12 available from SasolGermany GmbH of Witten, Germany). Another suitable low meltingsuppository base is hard fat having an ascending melting point of 33.5to 35.5° C. (e.g., Witepsol® H-15 available from Sasol Germany GmbH).The dispersion is preferably substantially homogenous.

Yet another embodiment of the invention is a mesalamine rectalsuppository comprising mesalamine having (i) (a) a tap density rangingfrom about 600 to about 800 g/L (as measured by USP <616>) and/or (b) asurface area of from about 0.1 to about 2.8 m²/g (or preferably fromabout 0.2 to about 2.8 m²/g, preferably from about 0.1 to about 1.3m²/g, or preferably from about 0.2 to about 1.3 m²/g) and (ii) a hardfat having an ascending melting point of 32 to 35.5° C. Typically, themesalamine is dispersed in the hard fat. According to one preferredembodiment, the hard fat has an ascending melting point of 32 to 33.5°C. Preferably, such a dispersion is substantially homogenous. The weightratio of mesalamine to hard fat preferably ranges from about 1:2 toabout 1:1.25.

Preferably, the aforementioned suppositories each release at least about75% by weight of the mesalamine contained in the suppository within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5. In one embodiment, at least about 80, 90, or 95%by weight of the mesalamine is dissolved within 2 hours. According toanother embodiment, at least about 80, 85, or 90% by weight of themesalamine is dissolved within 1 hour. According to yet anotherembodiment, at least 90% by weight of the mesalamine is dissolved within30 minutes.

One preferred method for determining the dissolution profile of asuppository containing from about 400 to about 600 mg mesalamine is byUSP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 7sinker turns in 0.2 M phosphate buffer at a pH of 7.5. In oneembodiment, a suppository of the present invention containing from about400 to about 600 mg (or up to about 800 mg) mesalamine releases at leastabout 75% by weight of the mesalamine contained in the suppositorywithin 2 hours of dissolution as measured with USP Apparatus #2 at 40°C., a paddle rotation speed of 125 rpm, and 7 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5. In another embodiment, at least about80, 85, 90, or 95% by weight of the mesalamine is dissolved within 2hours. According to another embodiment, at least about 80, 85, or 90% byweight of the mesalamine is dissolved within 1 hour.

Yet another method for determining the dissolution profile of amesalamine suppository is by USP Apparatus #2 at 40° C., a paddlerotation speed of 125 rpm, and from 2 to 8 sinker turns (e.g., with awire helix) in 0.2 M phosphate buffer at a pH of 7.5. For instance, theaforementioned suppositories can release at least about 75% by weight ofthe mesalamine contained in the suppository within 2 hours ofdissolution as measured with USP Apparatus #2 at 40° C., a paddlerotation speed of 125 rpm, and from 2 to 8 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5.

Yet another embodiment is a method of treating ulcerative colitis, suchas active ulcerative proctitis, in a patient in need thereof byadministering to the patient a mesalamine rectal suppository of thepresent invention. Preferably, the mesalamine suppository isadministered once a day and more preferably once a day at bedtime. Thesuppository is also preferably retained for one to three hours orlonger, if possible. The treatment can be brief, for example, once dailyfor three to twenty-one days, or can be longer, for example, once dailyfor three to six weeks.

Yet another embodiment is a method of determining a dissolutionparameter (such as dissolution rate or amount of drug dissolved after aspecified period of time) of a mesalamine rectal suppository, such as a500 mg, 1 g or 1.5 g mesalamine suppository, by measuring itsdissolution with USP Apparatus #2 at 40° C. and a paddle rotation speedof 125 rpm in 0.2 M phosphate buffer at a pH of 7.5. A sinker can becoiled around the suppository, for example, for 2 to 8 turns of wire(e.g., wire helix). According to a preferred embodiment, a sinker islightly coiled around the suppository, for example with only 3 turns ofwire helix (for example, for a suppository containing 800 mg or moremesalamine). According to another embodiment, a sinker is coiled aroundthe suppository with 7 turns of wire helix (for example, for asuppository containing 800 mg or less mesalamine). This dissolutionmethod produces results which are significantly more reliable and lessvariable than those produced by other dissolution methods, such asmethods 1 and 3 discussed in Examples 1 and 2.

Yet another embodiment is a method of preparing a mesalamine rectalsuppository by (A) providing a mesalamine rectal suppository, and (B)measuring the dissolution rate of the suppository with USP Apparatus #2at 40° C. and a paddle rotation speed of 125 rpm in 0.2 M phosphatebuffer at a pH of 7.5. A sinker can be coiled around the suppository,for example, for 2 to 8 turns of wire (e.g., wire helix). According to apreferred embodiment, a sinker is lightly coiled around the suppository,for example, with only 3 turns of wire helix (for example, for asuppository containing 800 mg or more mesalamine). According to anotherembodiment, a sinker is coiled around the suppository with 7 turns ofwire helix (for example, for a suppository containing 800 mg or lessmesalamine). Step (B) may include determining whether the suppositoryreleases at least about 75% by weight of the mesalamine within 2 hoursof dissolution. Step (B) may additionally or alternatively includedetermining whether the suppository releases at least about 85% byweight of the mesalamine within 1 hour of dissolution.

Yet another embodiment is a method of preparing a batch of mesalaminerectal suppositories (i.e., 2 or more suppositories) by (A) providing abatch of mesalamine rectal suppositories; and (B) measuring thedissolution rate of at least one suppository from the batch with USPApparatus #2 at 40° C. and a paddle rotation speed of 125 rpm in 0.2 Mphosphate buffer at a pH of 7.5. A sinker can be coiled around thesuppository, for example, for 2 to 8 turns of wire (e.g., wire helix).According to a preferred embodiment, a sinker is lightly coiled aroundthe suppository, for example, with only 3 turns of wire helix (forexample, for a suppository containing 800 mg or more mesalamine).According to another embodiment, a sinker is coiled around thesuppository with 7 turns of wire helix (for example, for a suppositorycontaining 800 mg or less mesalamine). Preferably, step (B) includesdetermining whether the suppository releases at least about 75 or 80% byweight of the mesalamine within 2 hours of dissolution (Q=75% asdescribed in USP 711 (30^(th) Ed.), the section entitled“immediate-release dosage forms”). Step (B) may additionally oralternatively include determining whether the suppository releases atleast about 85% by weight of the mesalamine within 1 hour ofdissolution. If the suppository does not meet the dissolution criterion,the batch of suppositories can be discarded.

Yet another embodiment is a method of preparing a mesalamine rectalsuppository by preparing the suppository from mesalamine having (i) (a)a tap density ranging from about 600 to about 800 g/L and/or (b) asurface area of from about 0.1 to about 2.8 m²/g (or preferably fromabout 0.2 to about 2.8 m²/g, preferably from about 0.1 to about 1.3m²/g, or preferably from about 0.2 to about 1.3 m²/g) with (ii) asuppository base, such as a hard fat, having an ascending melting pointof 32 to 35.5° C. (e.g., 32 to 33.5° C.). The inventors have found thatthe viscosity of a molten mixture containing mesalamine variessignificantly depending on the tap density of the mesalamine used toform the molten mixture. A molten mixture having a high viscosity (e.g.,greater than 5000 cps) has been found to have flow problems duringsuppository filling and caused small entrapped air bubbles to be moldedinto the surface of the suppository with content uniformity issues andresulting in an aesthetically less desirable product. The suppositorymay, for example, be prepared by (A) mixing the mesalamine having theaforementioned tap density with a suppository base having theaforementioned melting point, and (B) molding the mixture.

According to one embodiment, the mesalamine suppository is prepared by(A) melting the suppository base, e.g., to form a molten solution, (B)adding mesalamine to the melted suppository base, and (C) molding themixture.

Yet another embodiment is a mesalamine rectal suppository comprisingmesalamine particles and one or more pharmaceutically acceptableexcipients, where the mesalamine particles have a surface area of fromabout 0.1 m²/g to about 2.8 m²/g (or preferably from about 0.2 to about2.8 m²/g). According to one embodiment, the drug load of the suppositorypreferably ranges from 35% to 50% (or from about 37% to about 46%).Preferably, the mesalamine particles have a tap density ranging fromabout 600 to about 800 g/L (as measured by USP <616>). The suppositorycan release at least about 75% by weight of the mesalamine within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5. In another embodiment, the suppository canrelease at least about 75% by weight of the mesalamine within 2 hours ofdissolution as measured with USP Apparatus #2 at 40° C., a paddlerotation speed of 125 rpm, and from 2 to 8 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5. In yet another embodiment, thesuppository can release at least about 75% by weight of the mesalaminewithin 2 hours of dissolution as measured with USP Apparatus #2 at 40°C., a paddle rotation speed of 125 rpm, and 7 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5. In one embodiment, the surface area offrom about 0.1 or 0.2 m²/g to about 1.3 m²/g. In another embodiment, thesurface area of from about 1.3 m²/g to about 2.8 m²/g.

In one embodiment, the mesalamine suppository containing mesalamineparticles having a surface area of from about 0.1 m²/g (or 0.2 m²/g) toabout 2.8 m²/g releases

-   -   (a) between 15.0% and 95.1% (w/w) of the mesalamine after 10        minutes of dissolution,    -   (b) at least 27.9% (w/w) of the mesalamine after 20 minutes of        dissolution, and/or    -   (c) at least 32.5% (w/w) of the mesalamine after 30 minutes of        dissolution, as measured with USP Apparatus #2 at 40° C., a        paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M        phosphate buffer at a pH of 7.5. For example, the mesalamine        suppository contains 1 g or 1.5 g mesalamine.

In another embodiment, the mesalamine suppository contains mesalamineparticles having a surface area of from about 0.1 m²/g (or 0.2 m²/g) toabout 1.3 m²/g and releases

-   -   (a) at least 41.4% (w/w) of the mesalamine after 20 minutes of        dissolution, and/or    -   (b) at least 62.3% (w/w) of the mesalamine after 30 minutes of        dissolution, as measured with USP Apparatus #2 at 40° C., a        paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M        phosphate buffer at a pH of 7.5. For example, the mesalamine        suppository contains 1 g or 1.5 g mesalamine.

In yet another embodiment, the mesalamine suppository containsmesalamine particles having a surface area of from about 1.3 m²/g toabout 2.8 m²/g and releases

-   -   (a) between 19.1% and 40.3% (w/w) of the mesalamine after 10        minutes of dissolution,    -   (b) between 27.9% and 70.7% (w/w) of the mesalamine after 20        minutes of dissolution, and/or    -   (c) between 32.5% and 94.8% (w/w) of the mesalamine after 30        minutes of dissolution,        as measured with USP Apparatus #2 at 40° C., a paddle rotation        speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate buffer        at a pH of 7.5. For example, the mesalamine suppository contains        1 g or 1.5 g mesalamine.

Yet another embodiment is a mesalamine rectal suppository comprisingfrom 1.1 to 2.5 g mesalamine particles and one or more pharmaceuticallyacceptable excipients, where the mesalamine particles have (i) a surfacearea of from about 0.1 m²/g to about 2.8 m²/g, (ii) a tap densityranging from about 600 to about 800 g/L (as measured by USP <616>), or(iii) both. Preferably, the suppository releases at least about 85% byweight of the mesalamine within 1 hour of dissolution as measured withUSP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3sinker turns in 0.2 M phosphate buffer at a pH of 7.5. The drug load inthe suppository can be, for example, from 25% to 50% (for instance, 35%to 50%). The suppository can contain any of the aforementioned amountsof mesalamine, for instance, from about 400 mg to 3000 g of mesalamine.In one embodiment, the suppository contains about 400 to about 800 mgmesalamine. In another embodiment, the suppository contains from about1.1 to about 2.5 g mesalamine.

The suppositories of the present invention (including all of theembodiments mentioned above) can include, for example, from about 400 or500 mg to about 3 g of mesalamine. For instance, a suppository of thepresent invention can include 500 mg, 600 mg, 750 mg, 800 mg, or 1, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5g of mesalamine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the viscosity of the molten mixtures preparedin Example 3 versus the tap densities of the mesalamine used to preparethe molten mixtures.

FIG. 2 is a graph showing the viscosity of the molten mixtures preparedin Example 4 versus the tap densities of the mesalamine used to preparethe molten mixtures.

FIG. 3 is a graph showing the viscosity of the molten mixtures preparedin Examples 3 and 4 versus the tap densities of the mesalamine used toprepare the molten mixtures.

FIGS. 4-9 show the dissolution profiles of mesalamine suppositorieshaving drug loads of 33, 37, and 42% prepared from mesalamine having atap density of 680 or 730 g/L and hard fat having an ascending meltingpoint of 32 to 33.5° C. (Witepsol® H-12) or 33.5 to 35.5° C. (Witepsol®H-15).

FIG. 10 shows the dissolution profiles of mesalamine suppositorieshaving drug loads of 42 and 44% prepared from mesalamine having a tapdensity of 730 g/L and hard fat having an ascending melting point of 32to 33.5° C. (Witepsol® H-12).

FIG. 11A is a graph showing the percentage of mesalamine dissolved after30 minutes from mesalamine suppositories prepared in Example 7A at adrug load of 23% versus the surface area of the mesalamine, where thedissolution was measured with USP Apparatus #2 at 37.3° C., a paddlerotation speed of 100 rpm, and 7 sinker turns in 0.2 M phosphate bufferat a pH of 7.5.

FIG. 11B is a graph showing the percentage of mesalamine dissolved overtime from mesalamine suppositories prepared in Example 7B at a drug loadof 23%, where the mesalamine has various surface areas.

FIG. 12 is a graph showing the percentage of mesalamine dissolved frommesalamine suppositories prepared in Example 8 at a drug load of 33%versus the surface area of the mesalamine.

FIG. 13 is a graph showing the percentage of mesalamine dissolved overtime from mesalamine suppositories prepared in Example 8 at a drug loadof 33%, where the mesalamine particles in the suppositories have varioussurface areas.

FIG. 14 is a graph showing the percentage of mesalamine dissolved overtime from mesalamine suppositories prepared in Example 8 at a drug loadof 42%, where the mesalamine particles in the suppositories have varioussurface areas.

FIG. 15 is a graph showing the percentage of mesalamine dissolved overtime from mesalamine suppositories prepared in Example 9 at a drug loadof 39-42%, where the mesalamine particles in the suppositories havevarious surface areas.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “mesalamine” refers to 5-aminosalicylic acid (5-ASA). Accordingto one embodiment, the mesalamine has the following particle sizedistribution: X10 of about 5 to about 11 μm, X50 of about 25 to about 45μm, and X90 of about 85 to about 100 μm.

The term “drug load” refers to the weight percentage of mesalamine basedon the total weight of the suppository.

As used herein, the term “patient” refers to any mammal and preferably ahuman. The patient to be treated with mesalamine may in fact be anypatient of the human population, male or female, which may be dividedinto children, adults, or elderly. Any one of these patient groupsrelates to an embodiment of the invention.

As used herein, the term “treating” refers to preventing or delaying theappearance of clinical symptoms of a disease or condition in a patientthat may be afflicted with or predisposed to the disease or condition,but does not yet experience or display clinical or subclinical symptomsof the disease or condition. “Treating” also refers to inhibiting thedisease or condition, i.e., arresting or reducing its development or atleast one clinical or subclinical symptom thereof. “Treating” furtherrefers to relieving the disease or condition, i.e., causing regressionof the disease or condition or at least one of its clinical orsubclinical symptoms. The benefit to a patient to be treated is eitherstatistically significant or at least perceptible to the patient and/orthe physician.

Symptoms of active ulcerative proctitis include, but are not limited to,abdominal pain, diarrhea, rectal bleeding, sensation of incompleteemptying of the bowels, tenesmus, weight loss, fever, loss of appetite,tiredness, and other more serious complications, such as dehydration,anemia and malnutrition. A number of such symptoms are subject toquantitative analysis (e.g. weight loss, fever, anemia, etc.). Somesymptoms are readily determined from a blood test (e.g. anemia).

Unless otherwise specified, tap density is measured by the USP tappeddensity test <616>.

Formulations

The mesalamine (e.g., in powder form) is typically dispersed in asuppository base, such as hard fat. The suppository base can be an oilyor fatty base. Conventional suppository bases which may be employedinclude theobroma oil, hard fats, glycerides of fatty acids,glycerol-gelatin bases, and mixtures thereof. Suitable hard fat basesinclude, but are no limited to, esterified mixtures of mono-, di- andtriglycerides which are obtained by esterification of fatty acids(European Pharmacopoeia, 3rd edition 1997, Deutscher Apotheker VerlagStuttgart. p. 1022; The United States Pharmacopoeia, USP 23, NF18). Suchhard fats are commercially available, for example, under the nameWitepsol® (e.g. Witepsol® H12 and H15). A preferred suppository base ishard fat (e.g., hard fat NF).

Preferred hard fat bases include, but are not limited to, hard fatscontaining a mixture of mono-, di- and triglycerides of saturated C₉₋₁₈fatty acids. The hard fat base can comprise hard fats obtained byesterification of fatty acids of vegetable origin with glycerol, amacrogol ether containing 20 to 24 oxyethylene groups in thepolyoxyethylene chain, e.g., polyoxyl-20-cetostearyl ether, andglycerides, e.g., glyceryl ricinoleate.

Other suitable suppository bases include, but are not limited to, cocoabutter, lauric oil, beef tallow, hard fat, and any combination of any ofthe foregoing.

The drug load of the suppository is preferably 35 or 37% to 50%.According to one embodiment, the drug load ranges from about 37 to about46%. According to another embodiment, the drug load ranges from about 39to about 45%. According to yet another embodiment, the drug load rangesfrom about 41 to about 43%. For example, the suppository can containabout 1000 mg mesalamine dispersed in about 1300 to about 1500 mg of asuppository base (preferably hard fat).

The total weight of the suppository preferably ranges from about 2250 toabout 2700 mg and more preferably from about 2250 to about 2500 mg.According to one embodiment, the suppository has a total weight rangingfrom about 2300 mg to about 2500 mg.

The suppository is preferably smooth torpedo-shaped.

The melting point of the suppository is generally sufficient to melt inthe patient's body, and is typically no more than about 37° C.

Methods of Preparation

The mesalamine suppository of the present invention may be prepared asfollows. The mesalamine is dispersed in a suppository base in moltenform, which is then poured into a suitable mould, such as a PVC,polyethylene, or aluminum mould. For example, the mesalamine may bedispersed in the suppository base at a temperature of from about 35° C.to about 50° C. and preferably from about 40° C. to about 44° C. Themesalamine can be milled or sieved prior to incorporation into thesuppository base.

If desired, further pharmaceutically acceptable auxiliaries, such as,for example, stabilizers, consistency-improving additives or auxiliarieswhich bring about a uniform distribution of the mesalamine in thesuppository base, can be added. Optionally the suppositories may becoated, prior to packing, for example with cetyl alcohol, macrogol orpolyvinyl alcohol and polysorbates to increase disintegration time orlubrication or to reduce adhesion on storage.

Preferably, the viscosity of a sample of the molten mesalaminedispersion is determined in-process for quality control. For example,the viscosity cut off may be about 5000 to about 10000 cps. According toone embodiment, batches of molten mesalamine dispersion having aviscosity of about 10000 cps or less would be considered acceptablewhile those having a viscosity over 10000 cps would not (and, therefore,may be discarded). According to another embodiment, batches of moltenmesalamine dispersion having a viscosity of about 5000 cps or less wouldbe considered acceptable.

The tap density of the mesalamine used to prepare the molten mesalaminedispersion is also preferably monitored before production to ensure thatthe tap density of the mesalamine is at least about 600 g/L andpreferably from about 600 to about 800 g/L. Similarly, the surface areaof the mesalamine used to prepare the molten mesalamine dispersion ispreferably monitored before production to ensure that the surface areais in the desired range, e.g., between about 0.1 (or 0.2) and 2.8 m²/g(or between about 0.1 (or 0.2) and 1.3 m²/g, or between about 0.1 (or0.2) to about 0.8 m²/g, or between about 0.1 (or 0.2) to about 0.5 m²/g,or between about 0.6 to about 1.0 m²/g). Preferably, the mesalamine isnot in the form of granules suitable for compaction into tablets.Rather, the mesalamine is preferably in the form of a powder ofunagglomerated needle-shape crystals.

One or more sample suppositories from each batch produced are preferablytested by the dissolution method of the present invention for qualitycontrol. According to a preferred embodiment, a sample from each batchis tested to determine whether at least about 75 or 80% by weight of themesalamine dissolves within 2 hours.

Methods of Treatment

The mesalamine suppository can be administered to treat ulcerativecolitis, such as active ulcerative proctitis, in a patient in needthereof. Preferably, the mesalamine suppository is administered insufficient quantity and frequency to reduce the symptoms of ulcerativecolitis.

The mesalamine suppository can also be administered prophylactically toa patient at risk for ulcerative colitis (such as active ulcerativeproctitis). Preferably, the mesalamine suppository is administered insufficient quantity and frequency to delay or prevent the onset ofsymptoms of ulcerative colitis (e.g., to delay or prevent the onset ofabdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss ofappetite, dehydration, anemia, or malnutrition, or any combinationthereof).

In the above methods, the mesalamine suppository is preferablyadministered once a day and more preferably once a day at bedtime. Thesuppository is also preferably retained for one to three hours orlonger, if possible. The treatment can be brief, for example, once dailyfor three to twenty-one days, or can be longer, for example, once dailyfor three to six weeks.

The following examples illustrate the invention without limitation. Allpercentages are by weight unless otherwise indicated.

Example 1

The dissolution profiles of 1000 mg mesalamine suppositories (such asthose prepared according to the procedure described below) weredetermined by three different methods (shown in Table 1 below using USPApparatus #2). As discussed below, only the dissolution method of thepresent invention (method 2) produced consistent results.

TABLE 1 Parameter Method 1 Method 2 Method 3 Phosphate buffer 0.05 M 0.2M 0.2 M Temperature 37° C. 40° C. 37° C. Paddle rotation speed 100 rpm125 rpm 100 rpm Sinker turns 7 turns 3 turns 3 turns pH 7.5 7.5 7.5Preparation of 1000 mg Mesalamine Suppositories

1000 mg mesalamine suppositories were prepared by the followingprocedure. Add 200.0 kg of hard fat NF (Witepsol® 15) to a mix tank.Begin heating the batch to 58-62° C. by recirculating steam through thetank jacket. The target temperature is 60° C. Begin mixing with thesweeps at 12 Hz as the product begins to melt. Continue heating to58-62° C. (target 60° C.). Mix until the product is completely molten,increasing the sweeps to 60 Hz as the product melts. Mix for a minimumof 30 minutes, maintaining the temperature at 58-62° C. using the hotbox (target 60° C.). Adjust the temperature of the batch to 40-44° C. byrecirculating tap water at approximately 34-40° C. through the jacket.Maintain the batch at this temperature using the hot box (target 42°C.). While adjusting the temperature, shut off the sweeps, install theprop mixer with one 7″×7″ blade and restart the sweeps to 60 Hz. Beginmixing with the prop at 12 Hz and adjust the sweeps to 30 Hz.

Slowly add 100.0 kg of mesalamine powder USP to the mix tank. During theaddition of the powder, slowly increase the sweeps to 35 Hz and the propto 35 Hz as the product level in the tank increases, minimizingaeration. The addition of the powder is performed over a 35 to 60 minuteinterval.

Mix for a minimum of 60 minutes. During the mix period, flush productthrough the bottom valve using a large pot. Continue flushing throughoutthe mixing interval until product appears visually uniform. Return theproduct to the mix tank.

Adjust the temperature of the batch to 43-45° C. by recirculating tapwater at approximately 50-55° C. through the tank jacket or use the hotbox, if necessary. Perform in-process sampling from the bottom valve ofthe tank taking approximately 600 g in a plastic beaker. Hook up the hotbox and set it to hold the temperature of the batch at 43-45° C. Adjustthe sweeps to 30-36 Hz and prop to 20-30 Hz to prevent aeration of theproduct.

Fill each mould. Remove 1 suppository per filling head (14 consecutivesuppositories) every 25-35 minutes of operation. Fill weights ofindividual suppositories should be between 2.85 and 3.15 g.

Results

The dissolution profile of the 1000 mg mesalamine suppositories weredetermined by methods 1 and 2. The results are shown in Tables 2 and 3,respectively.

TABLE 2 Time Sample 1 Sample 2 Sample 3 10 min 10.5 11.8 11.3 20 min22.4 20.9 21.8 30 min 32.9 27.4 29.3 60 min 54.6 42.8 44.5 90 min 66.854.2 56.3 120 min  77.2 63 65.9 Average and SD 68.70% drug dissolved (SD= 7.50) (after 120 min)

TABLE 3 Time #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 Average SD  60 min92.2 93 96.8 93.7 93.4 93.2 92.8 93.8 84 97.2 94.4 96.6 93.4 3.4 120 min97.3 97.6 98.1 97.9 95.5 98.6 98.1 97.9 97.9 98.1 97.9 98.4 97.8 0.8 240min 97.5 98.2 97.7 97.2 97 98.6 98.1 97.3 97.8 97.3 97.2 97.8 97.6 0.5(SD = standard deviation)

The variability in the dissolution values after 120 minutes wassignificantly lower when measured by method 2 than when measured bymethod 1.

This low variability was further shown by dissolution tests usingmethods 2 and 3 performed on 1000 mg suppositories stored under normal(25° C. and 60% relative humidity) and accelerated (30° C. and 60%relative humidity) storage conditions. The results are provided inTables 4 and 5, respectively, and show that method 2 providesreproducible dissolution values with minimal intra-lot andbatch-to-batch variability.

TABLE 4 Time #1 #2 #3 #4 #5 #6 Average (%) SD Batch 1 (23.5 months, 25°C./60% RH)  60 min 97.8 96.8 98 99.2 98.2 98.6 98.1 0.8 120 min 98.798.9 98.5 99.2 98.3 98.2 98.6 0.4 240 min 98.3 98.5 98.1 98.6 97.5 987.798.1 0.4 Batch 2 (14.5 months, 25° C./60% RH)  60 min 97.6 97.5 98.298.2 97.6 97.1 97.7 0.4 120 min 97.1 97.5 97.9 97.9 98.3 97.2 97.7 0.5240 min 97.3 96.7 97.4 97.4 97.7 96.9 97.2 0.4 Batch 3 (4 months, 25°C./60% RH)  60 min 98.5 96.7 91 92.2 96.7 98.2 95.6 3.2 120 min 98.998.7 94.4 98.7 98.7 98.6 98.0 1.8 240 min 98.5 98.2 96 97.3 97.7 97.897.6 0.9 Batch 4 (2.5 months, 25° C./60% RH)  60 min 99.3 99.5 100.399.3 98.7 99.6 99.5 0.5 120 min 98.8 98.9 99.9 99.4 98.4 99.6 99.2 0.6240 min 98.5 98.9 99.4 98.6 97.8 99.1 98.7 0.6 Batch 5 (4.5 months, 25°C./60% RH)  60 min 100.8 101.7 101.3 101.4 101.3 101.4 101.3 0.3 120 min100.2 101.4 100.9 101 101.1 101.8 101.1 0.5 240 min 100.2 100.5 100.5100.5 100.8 101.1 100.6 0.3 Batch 6 (4.5 months, 25° C./60% RH)  60 min99.7 99.8 99.3 101.1 100 100.3 100.0 0.6 120 min 98.7 99.9 99.8 100.8100.1 100.1 99.9 0.7 240 min 98.5 99.4 99.7 100.6 99.8 99.4 99.6 0.7Batch 7 (4.5 months, 25° C./60% RH)  60 min 99.7 99.9 99.2 100.5 99.499.6 99.7 0.5 120 min 100 99.7 99.6 100.4 99.1 99.7 99.8 0.4 240 min99.7 99 99 99.5 98.7 98.8 99.1 0.4 Batch 8 (3.5 months, 30° C./60% RH) 60 min 100.8 100.3 100.7 101 101 100.7 100.8 0.3 120 min 100.6 99.9100.5 100.6 100.6 100.3 100.4 0.3 240 min 99.9 99.2 99.9 100 100 99.599.8 0.3 Batch 9 (3.5 months, 30° C./60% Rh)  60 min 100 99.9 100.2 99.799.8 99.8 99.9 0.2 120 min 99.7 99.4 100 99.4 100 99.5 99.7 0.3 240 min99.3 98.8 99.4 99 99.2 98.9 99.1 0.2 Batch 10 (3.5 months, 30° C./60%RH)  60 min 99.3 98.9 99.9 99.8 99.6 99.3 99.5 0.4 120 min 99.6 98.799.1 99.6 99.1 99.7 99.3 0.4 240 min 99.1 98.4 98.6 99.2 98.7 99.1 98.90.3

TABLE 5 Sample No. (within batch) Batch number and storage (samplestaken at 120 min) conditions 1 2 3 4 5 6 Average SD 11 101.5 102.4 102.5101.5 100.9 100.6 101.6 0.8 6 months at 25° C./60% RH 12 101.3 100.3101.3 102.3 100.3 100.0 100.9 0.9 6 months at 25° C./60% RH 13 100.499.7 98.6 100.3 98.8 99.8 99.6 0.8 6 months at 25° C./60% RH 14 98.299.3 98.9 97.2 99.1 98.8 98.6 0.8 25 months at 25° C./60% RH  15 92.498.4 97.6 97.3 96.7 92.0 95.7 2.8 16 months at 25° C./60% RH  16 98.496.4 95.5 96.8 99.6 96.9 97.3 1.5 5 months at 25° C./60% RH 17 99 98 97100 99 81 95.7 7.3 23 months at 25° C./60% RH  18 101 103 100 103 100102 101.5 1.4 23 months at 25° C./60% RH  19 101 102 101 103 100 102101.5 1.0 20 months at 25° C./60% RH  20 97 102 97 95 99 96 97.7 2.5 6months at 30° C./60% RH 21 94 94 72 81 91 106 89.7 11.8 6 months at 30°C./60% RH 22 85 92 93 89 94 75 88.0 7.2 6 months at 30° C./60% RH 23 8590 97 91 96 85 90.7 5.2 6 months at 30° C./60% RH 24 75 50 66 72 61 4060.7 13.4 6 months at 30° C./60% RH 25 73 97 60 89 87 81 81.2 13.1 6months at 30° C./60% RH

Samples from the three batches exhibiting the highest variability whenmeasured according to method 3, i.e., batches 21, 24 and 25, were testedby method 2 for comparison. The results are shown in Table 6.

TABLE 6 Sample No. (within batch) (samples taken at 120 min) Batch 1 2 34 5 6 Average SD 21 100 100 100 100 101 101 100.3 0.52 24 101 101 101101 101 102 101.2 0.41 25 100 100 101 100 99 100 100.0 0.63

These results show that method 2 produced more reliable and lessvariable dissolution results than method 3.

Example 2

The dissolution profiles of the 1000 mg mesalamine suppositoriesprepared in Example 1 were determined according to method 1 described inExample 1.

The results are shown in Table 7 below.

TABLE 7 1000 mg suppository At 120 min, Average: 73% + 10.3 (SD) Range:54.8%-97.1%

Example 3

The following experiment was conducted to determine if the tap densityof the mesalamine powder starting material significantly affected theviscosity of the molten mixture used to form the suppository. Generally,a molten mixture having a viscosity greater than about 5000 to about10000 cps was found to have flow problems during suppository filling andcaused small entrapped air bubbles to be molded into the surface of thesuppository with content uniformity issues and resulting in anaesthetically less desirable product.

The tap density of several lots of mesalamine were determined by USPtapped density test <616> and are shown in Table 8 below.

TABLE 8 Mesalamine Lot Tapped Density (g/ml) A 0.81 B 0.72 C 0.68 D 0.39E 0.68 F 0.46 G 0.60

Molten mixtures were prepared by the procedure described in Example 1using mesalamine lots A, B, and E. The molten mixtures had theviscosities reported in Table 9 below.

TABLE 9 Molten Mixture Mesalamine Tap Viscosity Lot No. Mesalmine LotDensity (g/ml) (cps) 1 A 0.81 429 2 B 0.72 468 3 E 0.68 1010

Molten mixtures prepared from combinations of mesalamine lots C-G wereprepared and had the viscosities reported in Table 10 below. Theindividual tap densities of each mesalamine lot were used to calculate acomposite tapped density (CTD) based on the amount of each lot. Thecalculated CTD can be expressed by the following equation:(CDF)₁+(CDF)₂+ . . . (CDF)_(n)=CTDwhere CTD=composite tapped density; CDF=contributed density factor=% oftotal drug used/100×TD; TD=measured tapped density; and n=number of druglots used.

TABLE 10 Molten Mixture Mesalamine Measlamine used TD CTD Viscosity LotNo. Lot (Kg) (g/ml) (g/ml) (cps) 4 C 82.5 0.68 D 17.5 0.37 0.62 1680 5 D61.0 0.37 E 17.0 0.68 F 22.0 0.46 0.44* 13300 6 G 100.0 0.60 0.60 1730*Note: Accuracy of the CTD of the 3 mesalamine lots used was confirmedby measuring the tap density of a separate mesalamine powder blend atthe same ratio. The result was 0.43 g/ml compared to 0.44 g/ml.

The density-viscosity data from Tables 9 and 10 were combined andplotted (FIG. 1) to assess the correlation for these two parameters.These data show a definite rank-order inverse relationship, with acorrelation coefficient of 0.9743. Notably, a reduction in the CTD from0.60 g/ml to 0.44 g/ml resulted in a 7 fold increase in viscosity from1730 cps to 13300 cps (see molten mixture lot nos. 5 and 6 in Table 10).

Example 4

The procedure described in Example 3 was repeated with mesalamine lotnos. 1-8 shown in Table 11 below. The results are shown in Table 11 andFIG. 2. From the correlation curve in FIG. 2, a viscosity of 5000 cpscorresponds to a tap density of about 0.50 g/ml.

TABLE 11 Mesalamine Lot No. Tap Density (g/ml) Viscosity (cps) 1 0.4513845 2 0.53 1755 3 0.44 19500 4 0.36 37100 5 0.40 47500 6 0.40 26910 70.36 37830 8 0.37 33735

The correlation of density to viscosity is essentially rank-order anddemonstrates an inverse relationship of the two parameters (correlationcoefficient=0.8803).

The tap density and viscosity data from Examples 3 and 4 (Tables 9-11)were combined and are shown graphically in FIG. 3. The combined dataclearly show the strong correlation (correlation coefficient=0.9343)between the tap density of mesalamine powder and its effect on thein-process viscosity of the drug-hard fat dispersions.

Example 5

1 g mesalamine suppositories using Witepsol® H-15 or Witepsol® H-12(hard fat NF) as the suppository base were prepared by the proceduredescribed in Example 1 at drug loads of 33, 37, 42, and 44%. All thesuppositories released at least 75% by weight of the mesalaminecontained in the suppository within 2 hours of dissolution as measuredwith USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5 (method #2 ofTable #1).

FIGS. 4 and 5 show the dissolution profiles of mesalamine suppositorieshaving drug loads of 33, 37, and 42% prepared from mesalamine having atap density of 680 g/L and Witepsol® H-15.

FIG. 6 shows the dissolution profiles of mesalamine suppositories havingdrug loads of 33, 37, and 42% prepared from mesalamine from Supplier 2,Grade B, having a tap density of 730 g/L and Witepsol® H-15.

The in-process molten mixtures of mesalamine and hard fat used in thepreparation of the suppositories described above with respect to FIGS. 4to 6 had the viscosities reported in Table 12 below. Suppositories couldnot be made from Grades C and D from supplier 2. Grades C and D weredesigned for compression of the mesalamine into tablets and were foundto be unsuitable for the preparation of a suspension in hard fat asrequired for the preparation of the suppository.

TABLE 12 Tap Dispersion Density Drug Load Viscosity Source g/L (% w/w)(Cps) Supplier 1 0.68 33 694 37 1131 42 2512 Supplier 2, grade A 0.68 33595 37 1084 42 2553 Supplier 2, grade B 0.73 33 515 37 845 42 1911Supplier 2, grade C 0.58 33 Too Viscous Supplier 2, grade D 0.91 33 PoorDispersion

FIG. 7 shows the dissolution profiles of mesalamine suppositories havinga drug load of 42% prepared from mesalamine having a tap density of 680g/L (supplied by Suppliers 1 and 2) or 730 g/L (Supplier 2, grade B) andWitepsol® H-15.

FIG. 8 shows the dissolution profiles of mesalamine suppositories havingdrug loads of 33% and 42% prepared from mesalamine having a tap densityof 680 g/L from supplier 1 and Witepsol® H-12 (ascending melting pointof 32 to 33.5° C.) or Witepsol® H-15 (ascending melting point of 33.5 to35.5° C.). It also compares suppositories having drug loads of 42%prepared with a mesalamine from supplier 2 having a tap density of 730g/ml manufactured using Witepsol® H-12 (ascending melting point of 32 to33.5° C.).

FIG. 9 shows the dissolution profiles of mesalamine suppositories havinga drug load of 42% prepared from mesalamine having a tap density of 680g/L (Supplier 1) or 730 g/L (Supplier 2, grade B) and Witepsol® H-12 orWitepsol® H-15.

FIG. 10 shows the dissolution profiles of mesalamine suppositories froma larger scale batch having drug loads of 42 and 44% prepared frommesalamine having a tap density of 730 g/L (Supplier 2, grade B) andWitepsol® H-12.

Example 6 High Density 1000 mg Mesalamine Suppositories

1 g mesalamine suppositories, each containing 1000 mg mesalamine (USP)and 1381 mg Witepsol® H-12 (hard fat NF), were prepared according to thefollowing procedure.

The hard fat (Witepsol® H-12, 65.25 kg) is melted by charging it into akettle, which is operated in automatic mode with a tank temperature of75° C., a melting temperature of 60° C., a cooling water temperature of48° C., a cooling air temperature of 44° C., a holding a T melting of 45minutes, a mixing at T melting of 15 minutes, and a holding at 256 rpmfor 60 minutes. When the temperature reaches 40-44° C., the mixing speedis between 60-80 rpm, and the water heating tank temperature is 71-79°C., the mesalamine from Supplier 2, grade B is slowly added over aperiod of 50 to 70 minutes with constant mixing at 230-270 rpm. Thesuspension is then mixed for 55 to 65 minutes (set point of 60 minutes)at 230-270 rpm. After the mixing time, the mixing speed is adjusted to168-180 rpm (set point of 175 rpm).

Moulds are then filled, each mould containing 2.33-244 g of thesuspension. The moulds are then cooled for 5 to 10 minutes at 20° C.

1 g suppositories heat sealed in PVC/PE containers (2.3 mL capacity percavity) were stored for at 25±2° C. and 60±5% relative humidity for 3months. The suppositories were found to be stable and release at least80% by weight of the mesalamine contained in the suppository within 2hours of dissolution as measured with USP Apparatus #2 at 40° C., apaddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphatebuffer at a pH of 7.5.

Example 7A

Suppositories containing 500 mg mesalamine having various surface areas,at a drug load of 23% were prepared by the procedure described inExample 1 using appropriate mixing speeds. The surface area of themesalamine ranged from 0.395 to 2.799 m²/g. The percentage of mesalaminedissolved at 30 minutes was measured with USP Apparatus #2 at 37.3° C.,a paddle rotation speed of 100 rpm, and 7 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5. The results are shown in FIG. 11A.

Example 7B

The percentage of mesalamine released over time was also measured foreach suppository, where the dissolution was measured with USP Apparatus#2 at 40° C., a paddle rotation speed of 125 rpm, and 7 sinker turns in0.2 M phosphate buffer at a pH of 7.5. The results are shown in FIG.11B.

Example 8

Suppositories containing 1000 mg mesalamine having various surface areasand Witepsol® H-15 (hard fat NF), at a drug load of 33% were prepared bythe procedure described in Example 1. The surface area of the mesalamineranged from 0.268 to 2.799 m²/g. The percentage of mesalamine dissolvedat 30 minutes was measured with USP Apparatus #2 at 40° C., a paddlerotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate bufferat a pH of 7.5. The results are shown in FIG. 12.

The percentage of mesalamine released after 10, 20, and 30 minutes wasalso measured for each suppository. The results are shown in FIG. 13.

Suppositories containing mesalamine having various surface areas andWitepsol® H-12 (hard fat NF), at a drug load of 42% were prepared by theprocedure described in Example 1. The surface area of the mesalamineused was 0.365, 0.731, or 1.393 m²/g. The percentage of mesalaminereleased over time was measured for each suppository. The results areshown in FIG. 14.

The tables below shows the minimum and maximum percentage of mesalaminedissolved as a function of surface area. The data presented in thetables originated from the 33% and 42% suppositories.

Minimum percentage of Minimum percentage of Minimum percentage ofSurface mesalamine dissolved mesalamine dissolved mesalamine dissolvedarea (m²/g) # batch after 10 min after 20 min after 30 min 1.3 < x < 2.84 26% 40% 52% 0.1 < x < 1.3 18 36% 59% 75%

Maximum percentage of Maximum percentage of Maximum percentage ofSurface mesalamine dissolved mesalamine dissolved mesalamine dissolvedarea (m²/g) # batch after 10 min after 20 min after 30 min 1.3 < x < 2.84 35% 59%  78% 0.1 < x < 1.3 18 77% 99% 105%

The following tables present the minimum specification based on theaverage value of mesalamine dissolved in the specified surface arearange and the maximum specification based on the average value ofmesalamine dissolved in the specified surface area range. The datapresented in the tables originated from the 33% and 42% suppositories.

Minimum percentage of Minimum percentage of Minimum percentage ofSurface mesalamine dissolved mesalamine dissolved mesalamine dissolvedarea (m²/g) # batch after 10 min after 20 min after 30 min 1.3 < x < 2.84 19.1% 27.9% 32.5% 0.1 < x < 1.3 18 15.0% 41.4% 62.3%

Maximum percentage of Maximum percentage of Maximum percentage ofSurface mesalamine dissolved mesalamine dissolved mesalamine dissolvedarea (m²/g) # batch after 10 min after 20 min after 30 min 1.3 < x < 2.84 40.3%  70.7%  94.8% 0.1 < x < 1.3 18 95.1% 111.5% 117.0%

The tables above as well as FIGS. 12-14 show that the dissolution rateof the mesalamine in suppositories with a drug load of 33 and 42% isincreasing with decreasing surface area. These results are contrary tothe general scientific understanding that greater surface area leads toa faster dissolution by increasing the wetability and the surfacecontact with the dissolution medium.

Example 9

Suppositories containing between 746 and 1460 mg mesalamine havingvarious surface areas (ranging from 0.395 to 2.799 m²/g) and Witepsol®H-12 (hard fat NF) (a drug load of 39-42%) were prepared by theprocedure described in Example 1, adjusted appropriately for the batchsize and apparatus used. Moulds were filled with each mould containingaround 3.5 g of the prepared suspension.

The percentage of mesalamine released after 10, 20, and 30 minutes wasmeasured for each suppository. The results are shown in FIG. 15.

All non-patent references, patents and patent applications cited anddiscussed in this specification are incorporated herein by reference intheir entirety and to the same extent as if each was individuallyincorporated by reference.

We claim:
 1. A mesalamine rectal suppository comprising from about 400to about 1600 mg mesalamine and an oily or fatty base, wherein themesalamine has a tap density ranging from about 600 to about 800 g/L (asmeasured by USP <616>), wherein the suppository has a drug load rangingfrom 35% to 50%, and the suppository releases at least about 75% byweight of the mesalamine within 2 hours of dissolution as measured withUSP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
 2. The mesalaminesuppository of claim 1, wherein the suppository comprises from about1450 to about 1550 mg of mesalamine.
 3. The mesalamine suppository ofclaim 1, wherein the oily or fatty base has an ascending melting pointranging from 32 to 33.5° C.
 4. The mesalamine suppository of claim 1,wherein the oily or fatty base has an ascending melting point rangingfrom 33 to 35.5° C.
 5. The mesalamine suppository of claim 1, whereinthe oily or fatty base is hard fat.
 6. The mesalamine suppository ofclaim 3, wherein the oily or fatty base is hard fat.
 7. The mesalaminesuppository of claim 1, wherein the drug load ranges from about 39 toabout 45%.
 8. The mesalamine suppository of claim 7, wherein the drugload ranges from about 41 to about 43%.
 9. The mesalamine suppository ofclaim 1, wherein the suppository releases at least about 80% by weightof the mesalamine within 2 hours of dissolution as measured with USPApparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinkerturns in 0.2 M phosphate buffer at a pH of 7.5.
 10. The mesalaminesuppository of claim 1, wherein the suppository releases at least about80% by weight of the mesalamine within 1 hour of dissolution as measuredwith USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
 11. Themesalamine suppository of claim 1, wherein the suppository releases atleast 90% by weight of the mesalamine within 30 minutes of dissolutionas measured with USP Apparatus #2 at 40° C., a paddle rotation speed of125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.12. A method of treating active ulcerative proctitis in a patient inneed thereof comprising administering the mesalamine rectal suppositoryof claim 1 to the patient.
 13. The method of claim 12, wherein themesalamine rectal suppository is administered once a day.
 14. The methodof claim 13, wherein the mesalamine rectal suppository is administeredonce a day at bedtime.
 15. A mesalamine rectal suppository comprisingfrom about 950 to about 1600 mg mesalamine and an oily or fatty base,wherein the mesalamine has a tap density ranging from about 600 to about800 g/L (as measured by USP <616>), and the suppository releases atleast about 75% by weight of the mesalamine within 2 hours ofdissolution as measured with USP Apparatus #2 at 40° C., a paddlerotation speed of 125 rpm, and 3 sinker turns in 0.2 M phosphate bufferat a pH of 7.5.
 16. The mesalamine rectal suppository of claim 15,wherein the suppository comprises from about 1450 to about 1550 mg ofmesalamine.
 17. The mesalamine rectal suppository of claim 15, whereinthe suppository comprises about 1500 mg of mesalamine.
 18. A mesalaminerectal suppository comprising from about 950 to about 1600 mg mesalamineand an oily or fatty base, wherein the suppository has a drug loadranging from 35% to 46%, and the suppository releases at least about 75%by weight of the mesalamine within 2 hours of dissolution as measuredwith USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
 19. Amesalamine rectal suppository comprising mesalamine particles and anoily or fatty base, wherein the mesalamine particles have a surface areaof from about 0.1 m²/g to about 2.8 m²/g, the suppository has a drugload ranging from 35% to 50%, and the suppository releases at leastabout 85% by weight of the mesalamine within 1 hour of dissolution asmeasured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5. 20.The mesalamine rectal suppository of claim 19, wherein the mesalamineparticles have a surface area of from about 0.1 m²/g to about 1.3 m²/g.21. The mesalamine rectal suppository of claim 19, wherein thesuppository comprises about 500 mg mesalamine.
 22. The mesalamine rectalsuppository of claim 19, wherein the suppository comprises about 1 gmesalamine.
 23. The mesalamine rectal suppository of claim 19, whereinthe suppository comprises about 1.5 g mesalamine.
 24. The mesalaminesuppository of claim 19, wherein the oily or fatty base has an ascendingmelting point ranging from 32 to 33.5° C.
 25. The mesalamine suppositoryof claim 19, wherein the oily or fatty base has an ascending meltingpoint ranging from 33 to 35.5° C.
 26. The mesalamine suppository ofclaim 18, the oily or fatty base is hard fat.
 27. The mesalaminesuppository of claim 19, the oily or fatty base is hard fat.
 28. Themesalamine suppository of claim 19, wherein the drug load ranges fromabout 39 to about 45%.
 29. The mesalamine suppository of claim 28,wherein the drug load ranges from about 41 to about 43%.
 30. Themesalamine suppository of claim 19, wherein the suppository releases atleast 90% by weight of the mesalamine within 30 minutes of dissolutionas measured with USP Apparatus #2 at 40° C., a paddle rotation speed of125 rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.31. The mesalamine rectal suppository of claim 20, wherein thesuppository releases (a) at least 41.4% (w/w) of the mesalamine after 20minutes of dissolution, and (b) at least 62.3% (w/w) of the mesalamineafter 30 minutes of dissolution, as measured with USP Apparatus #2 at40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5.
 32. A method of treating activeulcerative proctitis in a patient in need thereof comprisingadministering the mesalamine rectal suppository of claim 19 to thepatient.
 33. A mesalamine rectal suppository comprising mesalamineparticles and an oily or fatty base, wherein the mesalamine particleshave a surface area of from about 0.1 m²/g to about 2.8 m²/g, thesuppository has a drug load ranging from 35% to 50%, and the suppositoryreleases (a) between 15.0% and 95.1% (w/w) of the mesalamine after 10minutes of dissolution, (b) at least 27.9% (w/w) of the mesalamine after20 minutes of dissolution, and (c) at least 32.5% (w/w) of themesalamine after 30 minutes of dissolution, as measured with USPApparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinkerturns in 0.2 M phosphate buffer at a pH of 7.5.
 34. The mesalaminerectal suppository of claim 33, wherein the surface area of themesalamine particles ranges from about 1.3 m²/g to about 2.8 m²/g. 35.The mesalamine rectal suppository of claim 34, wherein the suppositoryreleases (a) between 19.1% and 40.3% (w/w) of the mesalamine after 10minutes of dissolution, (b) between 27.9% and 70.7% (w/w) of themesalamine after 20 minutes of dissolution, and (c) between 32.5% and94.8% (w/w) of the mesalamine after 30 minutes of dissolution, asmeasured with USP Apparatus #2 at 40° C., a paddle rotation speed of 125rpm, and 3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
 36. Amesalamine rectal suppository comprising mesalamine particles and anoily or fatty base, wherein the mesalamine particles have a surface areaof from about 0.1 m²/g to about 2.8 m²/g and a tap density ranging fromabout 600 to about 800 g/L (as measured by USP <616>), and thesuppository releases at least about 85% by weight of the mesalaminewithin 1 hour of dissolution as measured with USP Apparatus #2 at 40°C., a paddle rotation speed of 125 rpm, and 3 sinker turns in 0.2 Mphosphate buffer at a pH of 7.5.
 37. The mesalamine rectal suppositoryof claim 36, wherein the surface area of the mesalamine particles rangesfrom about 0.1 m²/g to about 1.3 m²/g.
 38. The mesalamine rectalsuppository of claim 36, wherein the suppository has a drug load rangingfrom 35% to 50%.
 39. The mesalamine rectal suppository of claim 36,wherein the suppository comprises about 500 mg mesalamine.
 40. Themesalamine rectal suppository of claim 36, wherein the suppositorycomprises about 1 g mesalamine.
 41. The mesalamine rectal suppository ofclaim 36, wherein the suppository comprises about 1.5 g mesalamine. 42.A mesalamine rectal suppository comprising from 1.1 to 2.5 g mesalamineparticles and an oily or fatty base, wherein the mesalamine particleshave (i) a surface area of from about 0.1 m²/g to about 2.8 m²/g, (ii) atap density ranging from about 600 to about 800 g/L (as measured by USP<616>), or (iii) both, and the suppository releases at least about 85%by weight of the mesalamine within 1 hour of dissolution as measuredwith USP Apparatus #2 at 40° C., a paddle rotation speed of 125 rpm, and3 sinker turns in 0.2 M phosphate buffer at a pH of 7.5.
 43. Amesalamine rectal suppository comprising mesalamine particles and anoily or fatty base, wherein the mesalamine particles have (i) a surfacearea of from about 0.1 m²/g to about 2.8 m²/g, (ii) a tap densityranging from about 600 to about 800 g/L (as measured by USP <616>), or(iii) both, the suppository having a drug load ranging from 25% to 50%,and the suppository releases at least about 85% by weight of themesalamine within 1 hour of dissolution as measured with USP Apparatus#2 at 40° C., a paddle rotation speed of 125 rpm, and 3 sinker turns in0.2 M phosphate buffer at a pH of 7.5.
 44. The mesalamine rectalsuppository of claim 43, wherein the suppository comprises about 400 toabout 800 mg mesalamine.
 45. The mesalamine rectal suppository of claim1, wherein the suppository is a moulded suppository.
 46. The mesalaminerectal suppository of claim 15, wherein the suppository is a mouldedsuppository.
 47. The mesalamine rectal suppository of claim 18, whereinthe suppository is a moulded suppository.
 48. The mesalamine rectalsuppository of claim 19, wherein the suppository is a mouldedsuppository.
 49. The mesalamine rectal suppository of claim 33, whereinthe suppository is a moulded suppository.
 50. The mesalamine rectalsuppository of claim 36, wherein the suppository is a mouldedsuppository.
 51. The mesalamine rectal suppository of claim 42, whereinthe suppository is a moulded suppository.
 52. The mesalamine rectalsuppository of claim 43, wherein the suppository is a mouldedsuppository.